Effexor (Venlafaxine) Drug Information

Venlafaxine Description, Indications, Side Effects, Warnings, Pharmacology, and Dosage
Antidepressant Basics

Generic Name: Venlafaxine
Brand Names: • Effexor • Effexor XR • Efexor

Class: Antidepressant, Serotonin/Norepinephrine Reuptake Inhibitor

Updated: July 2014

venlafaxine-effexor-pill-picture

What Is It?

EFFEXOR XR (VENLAFAXINE) is an antidepressant drug of the serotonin-norepinephrine reuptake inhibitor type. Effexor is distributed by Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.

What Does It Treat?

EFFEXOR XR is indicated and approved by the FDA for the treatment of:
• major depressive disorder
• generalized anxiety disorder
• social anxiety disorder
• panic disorder

Off-label uses include the treatment of:
• bipolar disorder
• fibromyalgia
• arthritis
• chronic fatigue syndrome
• multiple sclerosis
• lupus
• headaches
• irritable bowel syndrome (IBS)
• ADD/ADHD
• eating disorders

The efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for major depressive disorder was established in two placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depressive disorder. Your doctor will need to check your progress at regular visits while you are using Effexor XR. Your family or other caregivers should also be alert to changes in your mood or symptoms.

This medication guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about.

Do not start or stop any medicine while taking Effexor XR without talking to your healthcare provider first.

Who Should Not Take Effexor XR?

Do not take Effexor XR if you: 1) are allergic to venlafaxine or any of the ingredients in Effexor XR. See the end of this section for a complete list of ingredients in Effexor XR; 2) have uncontrolled angle-closure glaucoma; 3) take a monoamine oxidase inhibitor (MAOI) or have taken an MAOI in the past 14 days. Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. Do not take an MAOI within 2 weeks of stopping Effexor XR unless directed to do so by your physician. Do not start Effexor XR if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. MAOIs include Parnate (Tranylcypromine), Nardil (Phenelzine), Emsam (Selegiline transdermal), and Marplan (Isocarboxazid).

Safety and effectiveness in the pediatric population have not been established. Do not give Effexor XR to anyone younger than 18 years old without the advice of a doctor.

Before Starting Effexor XR

Tell your healthcare provider about: 1) any medical or psychiatric conditions you have, including cardiac, liver, kidney, or blood disease, seizures, or bipolar disorder; 2) current pregnancy or plans to become pregnant; 3) current breastfeeding or plans to breastfeed; 4) any and all medications and supplements you are taking; 5) any thoughts or feelings of suicide. Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Patients should be told that the concomitant use of Effexor XR and alcohol is not advised. Patients should inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions. Patients should notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should notify their physician if they are breast feeding an infant. While patients may notice improvement with Effexor XR therapy, they should be advised to continue therapy as directed.

Ingredients of EFFEXOR XR:

Active ingredient: venlafaxine. Inactive ingredients: Extended-Release Capsules: cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.

Indications and Usage

Major Depressive Disorder
Effexor XR (venlafaxine hydrochloride) extended-release capsules are indicated for the treatment of major depressive disorder. The efficacy of Effexor XR in the treatment of major depressive disorder was established in 8- and 12-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder. A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least five of the following nine symptoms during the same two-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The efficacy of Effexor (immediate release) in the treatment of major depressive disorder in adult inpatients meeting diagnostic criteria for major depressive disorder with melancholia was established in a 4-week controlled trial (see Clinical Trials). The safety and efficacy of Effexor XR in hospitalized depressed patients have not been adequately studied. The efficacy of Effexor XR in maintaining a response in major depressive disorder for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor (immediate release) in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial. Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Generalized Anxiety Disorder
Effexor XR is indicated for the treatment of Generalized Anxiety Disorder (GAD) as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The efficacy of Effexor XR in the treatment of GAD was established in 8-week and 6-month placebo-controlled trials in adult outpatients diagnosed with GAD according to DSM-IV criteria. Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. Although the effectiveness of Effexor XR has been demonstrated in 6-month clinical trials in patients with GAD, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Social Anxiety Disorder
Effexor XR is indicated for the treatment of Social Anxiety Disorder, also known as Social Phobia, as defined in DSM-IV (300.23). Social Anxiety Disorder (DSM-IV) is characterized by a marked and persistent fear of 1 or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person’s normal routine, occupational or academic functioning, or social activities or relationships, or there is a marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment. The efficacy of Effexor XR in the treatment of Social Anxiety Disorder was established in four 12-week and one 6-month placebo-controlled trials in adult outpatients with Social Anxiety Disorder (DSM-IV). Although the effectiveness of Effexor XR has been demonstrated in a 6-month clinical trial in patients with Social Anxiety Disorder, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Panic Disorder
Effexor XR is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, ie, a discrete period of intense fear or discomfort, in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) derealization (feelings of unreality) or depersonalization (being detached from oneself); 10) fear of losing control; 11) fear of dying; 12) paresthesias (numbness or tingling sensations); 13) chills or hot flushes. The efficacy of Effexor XR in the treatment of panic disorder was established in two 12-week placebo-controlled trials in adult outpatients with panic disorder (DSM-IV). The efficacy of Effexor XR in prolonging time to relapse in panic disorder among responders following 12 weeks of open-label acute treatment was demonstrated in a placebo-controlled study. Nevertheless, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Contraindications

Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation.

The use of MAOIs intended to treat psychiatric disorders with Effexor XR or within 7 days of stopping treatment with Effexor XR is contraindicated because of an increased risk of serotonin syndrome. The use of Effexor XR within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.

Starting Effexor XR in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.

Common Side Effects

Cardiovascular: Hypertension (3% to 13%)
Dermatologic: Sweating symptom (6.7% to 25% )
Endocrine metabolic: Weight loss (3% to 47% )
Gastrointestinal: Constipation (8% to 15% ), Loss of appetite (8% to 22% ), Nausea (21% to 58% ), Xerostomia (12% to 22% )
Neurologic: Asthenia (8% to 19% ), Dizziness (11% to 23.9% ), Dream disorder (3% to 7% ), Headache (25% to 38% ), Insomnia (14% to 24% ), Somnolence (14% to 26% ), Tremor (1.1% to 10.2% )
Ophthalmic: Blurred vision (4% to 6% )
Psychiatric: Feeling nervous (4% to 21.3% )
Reproductive: Abnormal ejaculation (2.2% to 19% ), Impotence (2.1% to 6% ), Orgasm disorder (2% to 5% )

Serious Side Effects

Endocrine metabolic: Hyponatremia
Gastrointestinal: Gastrointestinal hemorrhage (rare )
Hematologic: Bleeding, Abnormal
Hepatic: Hepatitis
Neurologic: Seizure (0.3% )
Psychiatric: Depression, exacerbation (rare ), Hypomania, Mania, Suicidal thoughts (rare ), Suicide
Other: Neuroleptic malignant syndrome, Serotonin syndrome

Get emergency medical help if you have any of these signs of an allergic reaction: skin rash or hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Suicidality and Antidepressant Drugs

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Effexor XR or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Effexor XR is not approved for use in pediatric patients.

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers.

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor XR is not approved for use in treating bipolar depression.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Effexor XR, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of Effexor XR with MAOIs intended to treat psychiatric disorders is contraindicated. Effexor XR should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking Effexor XR. Effexor XR should be discontinued before initiating treatment with the MAOI. If concomitant use of Effexor XR with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with Effexor XR and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including Effexor XR may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Sustained Hypertension

Effexor XR treatment is associated with sustained hypertension (defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive on-therapy visits. An analysis for patients in Effexor (immediate release) studies meeting criteria for sustained hypertension revealed a dose-dependent increase in the incidence of sustained hypertension for Effexor (immediate release). An insufficient number of patients received mean doses of Effexor XR over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses. In premarketing major depressive disorder studies, 0.7% (5/705) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 16 mm Hg, SDBP). In premarketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and 1.3% (7/535) of the Effexor XR-treated patients, respectively, discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 25 mm Hg, SDBP up to 8 weeks; 8 to 28 mm Hg up to 6 months). In premarketing Social Anxiety Disorder studies up to 6 months, 0.6% (5/771) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were modest (1–24 mm Hg, SDBP). In premarketing panic disorder studies up to 12 weeks, 0.5% (5/1001) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were in a modest range (7 to 19 mm Hg, SDBP). Sustained increases of SDBP could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving Effexor XR have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered.

Elevations in Systolic and Diastolic Blood Pressure

In placebo-controlled premarketing studies, there were changes in mean blood pressure. Across most indications, a dose-related increase in supine systolic and diastolic blood pressure was evident in Effexor XR-treated patients.

Overdose

Among the patients included in the premarketing evaluation of Effexor XR, there were 2 reports of acute overdosage with Effexor XR in major depressive disorder trials, either alone or in combination with other drugs. One patient took a combination of 6 g of Effexor XR and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of Effexor XR. This patient reported paresthesia of all four limbs but recovered without sequelae. There were 2 reports of acute overdose with Effexor XR in GAD trials. One patient took a combination of 0.75 g of Effexor XR and 200 mg of paroxetine and 50 mg of zolpidem. This patient was described as being alert, able to communicate, and a little sleepy. This patient was hospitalized, treated with activated charcoal, and recovered without any untoward effects. The other patient took 1.2 g of Effexor XR. This patient recovered and no other specific problems were found. The patient had moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. These symptoms resolved over the next week. There were no reports of acute overdose with Effexor XR in Social Anxiety Disorder trials. There were 2 reports of acute overdose with Effexor XR in panic disorder trials. One patient took 0.675 g of Effexor XR once, and the other patient took 0.45 g of Effexor XR for 2 days. No signs or symptoms were associated with either overdose, and no actions were taken to treat them. Among the patients included in the premarketing evaluation with Effexor (immediate release), there were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 μg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Call 911 or the Poison Help line at 1-800-222-1222 for all suspected overdose cases.

Pregnancy

Pregnancy Category C
Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Non-teratogenic Effects
Neonates exposed to Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. When treating a pregnant woman with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Labor and Delivery
The effect of venlafaxine on labor and delivery in humans is unknown.

Nursing Mothers
Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor XR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established. Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Effexor XR in a child or adolescent must balance the potential risks with the clinical need. Although no studies have been designed to primarily assess Effexor XR’s impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adversely affect weight and height. Should the decision be made to treat a pediatric patient with Effexor XR, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of Effexor XR treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration. In the studies conducted in pediatric patients (ages 6–17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients.

Geriatric Use

Approximately 4% (14/357), 6% (77/1381), 1% (10/819), and 2% (16/1001) of Effexor XR-treated patients in placebo-controlled premarketing major depressive disorder, GAD, Social Anxiety Disorder trials, and panic disorder trials, respectively, were 65 years of age or over. Of 2,897 Effexor-treated (immediate release) patients in premarketing phase major depressive disorder studies, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Effexor XR have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event. The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly. No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction.

Detailed Summary

Effexor XR is an extended-release capsule for oral administration that contains venlafaxine hydrochloride, a structurally novel antidepressant. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α- [(dimethylamino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. Effexor XR is formulated as an extended-release capsule for once-a-day oral administration. Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.

Pharmacodynamics

The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity.

Pharmacokinetics

Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively).

Absorption
Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45%. Administration of Effexor XR (150 mg q24 hours) generally resulted in lower Cmax (150 ng/mL for venlafaxine and 260 ng/mL for ODV) and later Tmax (5.5 hours for venlafaxine and 9 hours for ODV) than for Effexor (immediate release) [Cmax’s for immediate release 75 mg q12 hours were 225 ng/mL for venlafaxine and 290 ng/mL for ODV; Tmax’s were 2 hours for venlafaxine and 3 hours for ODV]. When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the Effexor XR capsule. Effexor XR, therefore, provides a slower rate of absorption, but the same extent of absorption compared with the immediate release tablet. Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM vs PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule.

Metabolism and Excretion
Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (“poor metabolizers”) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 (“extensive metabolizers”). The differences between the CYP2D6 poor and extensive metabolizers, however, are not expected to be clinically important because the sum of venlafaxine and ODV is similar in the two groups and venlafaxine and ODV are pharmacologically approximately equiactive and equipotent. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion.

Age and Gender
A population pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a patient is generally not necessary.

Extensive/Poor Metabolizers
Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV was similar in poor and extensive metabolizer groups, however, there is no need for different venlafaxine dosing regimens for these two groups.

Liver Disease
In 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. ODV elimination half-life was prolonged by about 60%, and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n = 11) subjects (mildly and moderately impaired, respectively). Venlafaxine oral bioavailability was increased 2–3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these hepatically impaired patients.

Renal Disease
In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR=10 to 70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR=10 to 70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56% compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients

Dosage and Administration

Dosage Forms and Strengths

Effexor XR (venlafaxine hydrochloride) extended-release capsules are available as follows:

• 37.5 mg, grey cap/peach body with W and “Effexor XR” on the cap and “37.5” on the body.
NDC 0008-0837-20, bottle of 15 capsules in unit of use package.
NDC 0008-0837-21, bottle of 30 capsules in unit of use package.
NDC 0008-0837-22, bottle of 90 capsules in unit of use package.
NDC 0008-0837-03, carton of 10 Redipak® blister strips of 10 capsules each.

• 75 mg, peach cap and body with W and “Effexor XR” on the cap and “75” on the body.
NDC 0008-0833-20, bottle of 15 capsules in unit of use package.
NDC 0008-0833-21, bottle of 30 capsules in unit of use package.
NDC 0008-0833-22, bottle of 90 capsules in unit of use package.
NDC 0008-0833-03, carton of 10 Redipak® blister strips of 10 capsules each.

• 150 mg, dark orange cap and body with W and “Effexor XR” on the cap and “150” on the body.
NDC 0008-0836-20, bottle of 15 capsules in unit of use package.
NDC 0008-0836-21, bottle of 30 capsules in unit of use package.
NDC 0008-0836-22, bottle of 90 capsules in unit of use package.
NDC 0008-0836-03, carton of 10 Redipak® blister strips of 10 capsules each.

The appearance of these capsules is a trademark of Wyeth Pharmaceuticals.

Major Depressive Disorder
For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In the clinical trials establishing the efficacy of Effexor XR in moderately depressed outpatients, the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. While the relationship between dose and antidepressant response for Effexor XR has not been adequately explored, patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4. In the clinical trials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; the average doses were about 140 to 180 mg/day. It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for Effexor (immediate release), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day). Whether or not higher doses of Effexor XR are needed for more severely depressed patients is unknown; however, the experience with Effexor XR doses higher than 225 mg/day is very limited.

Generalized Anxiety Disorder
For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Generalized Anxiety Disorder (GAD), the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in GAD was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days.

Social Anxiety Disorder (Social Phobia)
The recommended dose is 75 mg/day, administered in a single dose. There was no evidence that higher doses confer any additional benefit.

Panic Disorder
It is recommended that initial single doses of 37.5 mg/day of Effexor XR be used for 7 days. In clinical trials establishing the efficacy of Effexor XR in outpatients with panic disorder, initial doses of 37.5 mg/day for 7 days were followed by doses of 75 mg/day and subsequent weekly dose increases of 75 mg/day to a maximum dose of 225 mg/day. Although a dose-response relationship for effectiveness in patients with panic disorder was not clearly established in fixed-dose studies, certain patients not responding to 75 mg/day may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 7 days.

This dosage information does not include all the information needed to use Effexor XR safely and effectively. See full prescribing information for Effexor XR. The information at DepressionHealth.net is not a substitute for medical advice. ALWAYS consult your doctor or pharmacist.
This abridged guide is not the complete medication guide, and does not act as medical advice or replace the advice of a physician.
This guide is meant to be used as an educational tool and supplement to the expert advice and judgement of a physician.
Get emergency medical help or visit your nearest hospital if you have any of the signs of an allergic reaction when taking this medication:
skin rash or hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
If you overdose, seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of Effexor XR can be fatal.
The above information derives from the following sources: FDA Monograph Citation NDA020699, Micromedex®, MedlinePlus, DailyMed. Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed. Disclaimer: Every effort has been made to ensure that the information provided by Depression Health Network is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com